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LUPUS ERYTHEMATOSUS  

General aspects, diagnosis, and investigations

Lupus erythematosus (LE) is a multisystem disorder, which commonly affects the skin (sometimes in isolation). Possible effects on internal organs include renal, neurologic, cardiovascular, and lung disease. Some of the non-specific skin diseases that may occur is discussed more broadly elsewhere (e.g. vasculitis and diffuse alopecia). Aggravation by sunlight is frequent and may produce lesions resembling polymorphic light eruption (Fig.13.2); expression of autoantigens by keratinocytes may be induced by sunlight. The specific patterns of skin involvement may differ according to the category of LE (Table 13.2) and are discussed below; the most important patterns numerically are discoid (DLE), subacute cutaneous (SCLE) and systemic (SLE).

In all types of LE (except the neonatal form), there is a female predominance, which is most marked in SLE. About 5–10% of patients meet criteria for SLE (Table 13.3).

Investigations

Investigations in LE are to establish the diagnosis, and to determine the presence and degree of internal organ involvement; the following may all be pertinent.

Biopsy of skin lesions

This may show characteristic features, including a rather lichenoid dermo–epidermal junction infiltrate with basal keratinocyte vacuolation, which extends down the hair follicles. There is keratotic plugging of the follicles, most marked in chronic DLE. Rarely, the basal vacuolation may be sufficiently severe to cause clinically apparent blisters, usually in patients with acute cutaneous or subacute cutaneous LE.

Direct immunofluorescence studies on a skin biopsy (see Ch.16 for details of the technique and further reading) may show deposits of IgG, complement C3, IgM, or IgA in the basement membrane zone in lesional skin, less commonly in sun-exposed non-lesional skin, and least commonly (the lupus band test) in non-exposed skin.

Tests for autoantibodies

Antinuclear antibody is often positive in patients with collagen vascular disorders, and is therefore useful as a screening test, but it has varying degrees of sensitivity and specificity between diseases. Various patterns of nuclear staining may occur.

The ANA and other relevant antibodies, and their approximate frequency in different diseases, are listed in Table 13.4. Some antibodies are very specific to a particular disease or subset, even though they may occur only in a minority of patients (e.g. Sm in SLE). Others may be demonstrated in several disorders but have a particularly strong link with a particular disease, such as anticentromere antibodies with CREST, anti-RNP antibodies with MCTD, or antihistone antibodies with drug-induced LE.

  Anti-SSA (anti-Ro) and anti-SSB (anti-La) are extractable nuclear antigens, which may be present in photosensitive, subacute cutaneous, neonatal, and late-onset LE, and in Sjögren syndrome (from which the ‘SS’ is derived), dermatomyositis (uncommonly), and others. SSA may produce positive tests in patients with ANA-negative LE, the combination of negative ANA and positive SSA being found particularly in SCLE and neonatal LE.

    Antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) may be linked with LE but are discussed in the section on antiphospholipid syndrome (Ch.14), as they also occur without background LE. A skin lesion that can rarely occur in patients with LE, anetoderma, may be more common in patients with antiphospholipid antibodies.

Complement levels

These should be tested in patients with active LE. Complement C4 levels are often subnormal in patients with active systemic disease. Low levels are particularly linked with renal involvement. Occasional patients have familial LE due to inherited complement deficiency (usually C2 or C4), and there is an association with C1 esterase inhibitor deficiency, which causes hereditary angioedema.

Tests for involvement of internal organs

Tests for internal organ involvement may include urinalysis (proteinuria and casts), electrolytes, full blood count, liver function tests, erythrocyte sedimentation rate (ESR), and others, as determined by symptoms.

Drug-induced lupus

A wide range of drugs may provoke LE or LE-like eruption (Fig. 13.3).

Fig. 13.3 Lupus erythematosus: it was uncertain whether the disease was drug-induced, due to anticonvulsant therapy, or idiopathic. The clinical appearances are those of livedo (see Ch. 14), histologically with vasculitis. Serology was positive for antinuclear antibody, antihistone antibodies (a feature consistent with a drug etiology), and anti-dsDNA antibodies. (Courtesy of Dr. L. Barco.)

In some cases, patients may have a positive ANA test but no clinical symptoms (such as the majority of cases due to procainamide); even in symptomatic patients, anti-dsDNA and hypocomplementemia are rare in drug-induced LE. Sometimes, it may be difficult to be certain whether LE in a patient taking a relevant drug is actually drug-induced or idiopathic; the presence of antihistone antibodies suggests the possibility of drug-induced LE but is not specific. Patients with drug-induced LE typically have a photosensitive rash. Relevant drugs include the following.

Discoid lupus erythematosus

Discoid lupus erythematosus is the most common form of LE (Figs 13.4 – 13.14). It may occur as one of several features leading to a diagnosis of SLE, but commonly DLE lesions occur in the absence of other evidence of LE. Discoid lesions are erythematous, thickened plaques with scaling and plugging of follicles.

    They later become atrophic, scarred (including permanent loss of hair), telangiectatic, and variably pigmented. Most occur at sun-exposed facial sites, including the scalp (Figs 13.9–13.11). Ears are often affected (Fig. 13.12), as is the nasal tip (Fig. 13.13) and the lips more rarely (Fig. 13.14). Less commonly, annular (erythema multiforme-like) lesions may occur.
    About 20–30% of patients with DLE have positive ANAs, but fewer than 10% progress to develop SLE.

Systemic lupus erythematosus

Classification as SLE is made by fulfilling four of a series of diagnostic criteria proposed by the American Rheumatism Association (Table 13.3), although these criteria were proposed for use in clinical studies and do not preclude the diagnosis being made on the basis of fewer criteria in clinical practice (especially as there is no requirement for four criteria to be simultaneous). Additionally, some less specific criteria are not included (such as malaise, alopecia, or nail fold telangiectasia), some clinical patterns that strongly suggest LE are not included (e.g. hypocomplementemic urticarial vasculitis), and some supportive antibody tests (e.g. anti-SSA and antiphospholipid antibody) were not included at the time the criteria were proposed. The dermatologic manifestations included in the SLE diagnostic criteria are a ‘butterfly’ malar rash (Figs 13.15 and 13.16), DLE, and photosensitivity; other cutaneous features that were not specific enough to form part of the diagnostic criteria include diffuse alopecia (Fig. 13.17), nail fold telangiectasia (Fig.13.18), urticarial lesions (Fig. 13.19), and vasculitis (Fig. 13.20).

    By contrast with DLE, the acute malar rash of SLE often parallels disease in other organ systems. This is of diagnostic benefit, as it is very unlikely that malar rash in an otherwise completely well patient is due to SLE; in such patients, other diagnoses, such as rosacea (Fig.13.21), seborrheic dermatitis, contact dermatitis, and polymorphic light eruption should be considered. ANA tests are also more useful than in DLE, as they are positive in almost all patients with SLE, and over 50% with acute SLE also have anti-dsDNA antibodies, especially if there is active nephritis.

Subacute cutaneous lupus erythematosus

This variant of LE (Figs 13.22 – 13.27) is characterized by psoriasiform or annular skin lesions, photosensitivity, and mild systemic disease (usually arthritis). There is some overlap with SLE at the more severe end of the spectrum, and with DLE in other cases. A common feature is the demonstration of a negative ANA test but a positive anti-SSA (anti-Ro) antibody in serum; additionally, particulate intraepidermal IgG positivity on direct immunofluorescence testing of skin biopsies may reflect binding of anti-SSA antibodies to keratinocytes.

    Subacute cutaneous lupus erythematosus may be provoked by drugs, especially thiazides, and may occur in families with inherited complement deficiency or hereditary angioedema.

Chilblain lupus erythematosus

Chilblain (perniotic) LE is felt to be rare in the USA but more common in the UK (Figs 13.28 and 13.29). Patients have lesions around the nail folds of fingers and toes, often duskiness and hyperkeratosis of fingers and feet, and sometimes annular lesions of the limbs. Histologically, they have features of DLE. They are very refractory to treatment, but may respond to vasodilators as used for the treatment of Raynaud phenomenon.

Lupus erythematosus tumidus

It is unclear whether this should be treated as a separate variant of LE, but it does have some features that are different from more typical DLE. These include an acute and seasonal (summer) presentation, localized tumid lesions, marked photosensitivity, and good response to systemic antimalarials.

Lupus panniculitis

This is also known as lupus profundus (Figs 13.30 and 13.31). It is most common in women with LE, presenting as firm, inflamed nodules that may form a contracted scar with depression of the overlying skin surface.

Mucosal lupus erythematosus

Mucosal lesions are probably underestimated. Lips are not uncommonly affected in patients with DLE. Palatal lesions (Fig.13.32) and rather lichenoid-appearing buccal and gingival lesions (Fig. 13.33) may all be present.

Neonatal lupus erythematosus

This disorder is due to transplacental transfer of antibodies, most commonly anti-SSA but less commonly anti-SSB alone or anti-U1RNP. The mother may be asymptomatic, have Sjögren syndrome, or have SCLE, but will have positive antibodies (the diagnosis is usually confirmed by testing maternal blood). Skin lesions in the neonate are typically mild, usually annular, erythematous plaques, which resemble mild SCLE. They occur especially on the face and scalp (Fig. 13.34), typically involving the periorbital area (‘owl eye’ appearance), although limbs and trunk can also be affected. Crusting may be prominent, and photosensitivity is common, although not always clinically apparent. Telangiectasia, cutis marmorata, or angiomatous lesions may occur in the absence of more typical rash.

    The important systemic feature that may occur is neonatal heart block, which may be detected from about the 20th week of pregnancy. By contrast to the skin lesions, which resolve spontaneously in the first 6 months postpartum, the heart block does not resolve. However, even in women with known SLE and anti-SSA antibodies, the risk is only about 10–20%. Other systemic involvement is uncommon, apart from thrombocytopenia. Systemic involvement may have a male predominance.

Differential diagnosis

This is indicated, by clinical pattern, in Table 13.2.

PRACTICE POINTS

Treatment

Sunscreens are important therapeutically in all types of LE, especially SCLE and tumid LE. UVB-blocking ability is usually felt to be the most important factor, although there are cases of LE provoked by UVA tanning sunbeds, and about half of the patients with LE in whom lesions can be artificially photoprovoked react in both the UVA and UVB ranges (see also Ch.17).

    The usual treatment for discoid lesions is a potent topical corticosteroid. Although these have potential risks of skin atrophy on the face, this is balanced against the potential for permanent scarring, particularly scarring alopecia in the beard area or scalp. Intralesional steroid injections may be useful for refractory discoid lesions, or isolated areas of LE profundus. Topical tacrolimus has recently been documented to be useful in DLE, and avoids the risk of corticosteroid atrophy (Fig. 13.35). SCLE or SLE may also require topical treatment along the same lines, but systemic therapy is also often required.

    Antimalarials, usually hydroxychloroquine, are a useful adjunct to topical therapy in patients with troublesome DLE, in many patients with SLE (especially if photosensitivity is prominent), and especially in SCLE. They also appear to be useful in patients with thrombotic risk due to antiphospholipid syndrome (Fig.13.36 and Ch.14). Headache and nausea are the most common side effects, but most patients tolerate these drugs well. Hydroxychloroquine dosage should not be above 6.5mg/kg lean body mass, as this increases the risk of ocular toxicity (chronic maculopathy). Mepacrine (Atabrine) does not have this ocular risk but causes yellowish or gray pigmentation (especially of palate and sclerae), and may cause a lichenoid drug eruption. In some patients, the two antimalarials used together appear to produce better results than either alone. Smoking markedly decreases the benefit from antimalarials: patients should be advised to stop.

    In SLE, a variety of systemic agents may be used that are not usually necessary for the other types of LE. Systemic steroids should be started in acute severe LE on clinical suspicion, and adjusted on the basis of clinical response.
Azathioprine is commonly used as an immunosuppressive agent in SLE. It is generally well tolerated but causes dose-related hematologic toxicity (see Ch.4 for details on use of azathioprine). Long-term azathioprine immunosuppression predisposes to skin cancers (see Chs 12 and 32), and hence is another reason for sun-avoidance measures in patients with LE.
    Other immunosuppressive agents that may be used in LE include dapsone, methotrexate, gold, cyclophosphamide, retinoids, interferon, ciclosporin, pulsed methylprednisolone, intravenous gamma-globulin, thalidomide, and clofazimine. Dapsone produces a rapid response in patients with a rare bullous form of LE in which blisters arise on clinically normal skin, and is also useful in SCLE. Other agents, such as antihypertensives, are also commonly required for the systemic manifestations.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.